The Brugada syndrome

Gerald V. Naccarelli, MD*, Charles Antzelevitch, PhD, Deborah L. Wolbrette, MD*,

and Jerry C. Luck, MD*

The Brugada syndrome describes a subgroup of patients at

risk for the occurrence of ventricular fibrillation who have no
definable structural heart disease associated with a right
bundle branch block conduction pattern and ST-segment
elevation in the right precordial leads. This syndrome is
caused by genetic defects in the alpha subunit of the sodium
channel. This defect causes a reduction in the sodium channel
current, which accentuates the epicardial action potential
notch leading to ST-segment elevation. Sodium channel
blockers can potentiate these findings and screen for patients
with intermittent baseline electrocardiographic findings.
Because of the poor prognosis of such patients, symptomatic
patients should be treated with an implantable cardioverterdefibrillator. Curr Opin Cardiol 2002, 17:1923 2002 Lippincott Williams
& Wilkins, Inc.

*Division of Cardiology, Cardiovascular Center, Penn State University College of

Medicine, Hershey, Pennsylvania; Masonic Medical Research Laboratory, Utica,
New York, USA.
Correspondence to Gerald V. Naccarelli, MD, Professor of Medicine, Chief,
Division of Cardiology, Director, Cardiovascular Center, Penn State University
College of Medicine, 500 University Drive, H047, Hershey, PA 17033, USA
Current Opinion in Cardiology 2002, 17:1923
ISSN 02684705 2001 Lippincott Williams & Wilkins, Inc.

Approximately 5% of patients who experience sudden

cardiac death have no demonstrable structural heart disease or obvious cause and are classified as having idiopathic ventricular fibrillation [1,2]. A subgroup of patients with idiopathic ventricular fibrillation has been
shown to manifest a right bundle branch block (RBBB)
pattern and ST-segment elevation in leads V1 to V3.
Such patients die commonly in their sleep, secondary to
ventricular fibrillation. This constellation of findings has
been labeled the Brugada Syndrome [3]. This disorder is often inherited with an autosomal dominant mode
of transmission. The only mutations thus far linked to
the syndrome appear in the gene that encodes for the
subunit of the sodium channel, SCN5A [4,5,6,
714,15]. This review discusses the molecular abnormalities, cellular basis, ionic alterations, clinical evaluation, and treatment of this syndrome.

Molecular genetics of Brugada syndrome

About 20 to 25% of Brugada patients have documented
SCN5A mutations [14]. Genetic studies have demonstrated that some cases of Brugada syndrome and chromosome 3-linked long-QT syndrome are allelic disorders
of the cardiac sodium channel gene (SCN5A, 3p21).
Three types of SCN5A mutations have been identified
in the Brugada syndrome: splice-donor, frame-shift, and
missense [4,14,15]. All of these mutations lead to a
reduction in the fast sodium channel current.

Cellular basis for the Brugada syndrome

Under normal conditions, the presence of a transient outward current (Ito) mediated action potential notch or
spike and dome morphology in ventricular epicardium,
but not endocardium, creates a transmural voltage gradient responsible for the electrocardiographic J wave elevation [16]. A reduction in the density of the sodium
channel current as occurs with the inherited mutations
discussed previously, is known to accentuate the epicardial action potential notch leading to ST-segment elevation secondary to the accentuation of the transmural voltage gradients normally responsible for inscription of the
J wave. If the epicardial repolarization precedes repolarization of the cells in M and endocardial regions, the T
wave remains positive, causing a saddleback form of STsegment elevation. Additional reduction of INa causes
further accentuation of the notch accompanied by a prolongation of the epicardial action potential such that the
direction of the transmural voltage gradient is reversed,
thus leading to the development of a coved-type of ST19

20 Arrhythmias

segment elevation and inversion of the T wave. A delay

in epicardial activation can also contribute to inversion of
the T wave. Although the typical Brugada morphology is
present at this juncture, the substrate for reentry is not.
A further shift in the balance of currents leads to loss of
the action potential dome at some epicardial sites, which
manifests as further ST-segment elevation. Loss of the
action potential dome in epicardium but not endocardium results in the development of a marked transmural
dispersion of repolarization, which is responsible for the
development of a vulnerable window during which an
extrasystole can induce a reentrant arrhythmia. The loss
of the epicardial action potential dome at some sites but
not others creates a dispersion of repolarization within
epicardium [17]. Propagation of the action potential
dome from sites at which it is maintained to sites at
which it is lost causes local re-excitation via a phase 2-reentry mechanism. This causes the development of a very
closely coupled extrasystole, which is capable of initiating circus movement reentry [1719].

Class I agents expressing Brugada syndrome

electrocardiographic abnormality
The use of sodium channel blockers, in an already diseased sodium channel, can facilitate loss of the epicardial
action potential dome and slowing conduction and provoke the appearance of an RBBB pattern and ST elevation and spontaneous premature ventricular contractions,
ventricular tachycardia/fibrillation [6,7,11,2024]. Sodium channel blockade facilitate the loss of the right
ventricular epicardial action dome by shifting the balance of current at the end of phase I of the action potential from inward to outward and further diminish INa
already reduced by Brugada mutations that speed up
inactivation of INa. Premature inactivation of the early
current can leave Ito unopposed in the epicardium of the
right ventricle, which has a denser Ito current than the
left ventricular myocardium [16]. This more dense current will cause a transmural voltage gradient that manifests itself as ST-segment elevation in the right precordial leads [25,26].
Because of the pivotal role of the transient outward current, agents that block Ito, such as quinidine, have been
shown to restore the action potential dome and electrical
homogeneity, thus suppressing all arrhythmic activity in
experimental models [17,26]. Agents that potently block
INa, but not Ito (flecainide, ajmaline and procainamide),
exacerbate or unmask the Brugada syndrome, whereas
those with actions to block both INa and Ito (eg, quinidine and disopyramide) may exert a therapeutic effect
[17]. The anticholinergic effects of quinidine may also
contribute to its effectiveness. In patients with the Brugada syndrome, anecdotal evidence exists for an ameliorative effect of quinidine, an agent with Ito blocking
actions [2528].

Clinical genetics of Brugada syndrome

Patients are usually male, white and Asian with no reported cases in black Africans. In 25% of patients, the
genetics are unclear and in 15% there is no family history; these cases may represent sporadic mutations. In
the Brugada syndrome, up to 25% of families have apparent autosomal dominant inheritance with variable expression of the abnormal gene [29]. Approximately 50%
of offspring of affected patients develop the disease.

Clinical aspects of Brugada syndrome

Osher and Wolff [30] first identified the electrocardiographic pattern of RBBB with ST-elevation in leads V1
to V3. In 1992, Josep and Pedro Brugada described 8
patients with a history of aborted sudden death and a
distinct pattern of RBBB, ST-segment elevations in the
right precordial leads, a normal QT interval in the absence of any structural heart disease [3]. In 4 of the 8
patients, a family history was suggested. The above electrocardiographic findings associated with sudden death
have also been reported as a common problem in Japan
and Southeast Asia commonly affecting men during
sleep [31,32,33] and labeled as Sudden and Unexpected
Death Syndrome (SUDS) or Sudden Unexpected Nocturnal Death Syndrome (SUNDS). This syndrome probably is the same as Brugada syndrome because the ECG
in these patients typically displays an RBBB morphology, and a precordial injury pattern in V1 through V3.
Medical histories and physical examinations of these patients are unremarkable. In a review of 163 cases, males
(N = 150) far outnumbered females (N = 13) [30] and
58% of patients were of Asian ancestry. A family history
of syncope, documented ventricular fibrillation or sudden death was reported in 22% of the population. Among
the 104 patients who presented with symptoms, 76 had
ventricular fibrillation and 28 had syncope. The remaining patients in this series had the typical electrocardiographic findings noted during screening of family members of the proband. Of 21 patients whose activity was
reported at the time of their arrhythmic event, 17 occurred at rest or during sleep.

Electrocardiographic findings
The typical electrocardiographic findings [3,6,34] of
the Brugada syndrome suggest premature repolarization
and/or conduction delay in the right ventricle as noted by
the ST-segment elevation in the right precordial leads.
The ST-segment elevation is typically down sloping and
followed by a negative T wave. No reciprocal STsegment depression is noted in most cases of the Brugada syndrome. Widened S waves in the lateral leads are
usually absent, suggesting the absence of a true right
bundle branch block.
The presence of the above electrocardiographic findings
was present in 0.05% of 22,027 subjects in one study [35],

The Brugada syndrome Naccarelli et al. 21

in 0.1% on another study of 3585 [36], and in 0.16% of

10,000 asymptomatic subjects in a recent study [37].
What percentage of these patients truly has Brugada syndrome versus a normal electrocardiographic variant is not
known. Because the electrocardiogram can normalize
transiently in up to 40% of cases, this intermittent nature
of these findings can make diagnosis of the Brugada syndrome difficult. Sodium channel blocking agents such as
ajmaline, procainamide, flecainide, and propafenone can
accentuate the changes and be used as a diagnostic test
[6,7,11,2024]. Class IB agents, which are weak sodium channel blockers, appear to have no effect on the
ST-segment elevation. Class IA or IC sodium channel
blocker challenge can cause spontaneous ventricular fibrillation. Beta-blockade worsens while beta-stimulation
(stress testing and isoproterenol) usually ameliorates STsegment elevation [6,20].

Evaluation
A detailed family history is critical [30,38]. A history of
unexplained syncope or rapid palpitations with presyncope is concerning. Because 50% of cases are familial, a
resting ECG can be diagnostic because it can demonstrate the classic RSR prime pattern and ST-segment
elevation in the precordial leads. However, because 50%
of cases are concealed, the resting ECG may not be diagnostic. Ruling out left ventricular dysfunction and arrhythmogenic right ventricular dysplasia by noninvasive
imaging [38] or obstructive coronary artery disease in
older patients is important. Recently, electron beam cardiac tomography demonstrated morphologic abnormalities in the right ventricle in 21 of 26 (81%) of Brugada
syndrome patients [39]. The majority of the abnormalities were in the right ventricular outflow tract with some
abnormalities noted in the right inferior wall. In patients
with spontaneous premature ventricular contractions,
there was a reasonable association of their focus to the
anatomic site noted in the abnormal scan. Holter and
stress testing may depict frequent premature ventricular
complexes or nonsustained polymorphic ventricular
tachycardia. In the Brugada syndrome, polymorphic ventricular tachycardia is often very rapid and the precipitating extrasystole is short-coupled, which may differentiate this syndrome from torsade de pointes. About 10%
of Brugada syndrome patients have concomitant atrial
fibrillation. An association with supraventricular tachycardias has been reported [40]. Electrophysiologic testing often reveals easily inducible sustained polymorphic
ventricular tachycardia or ventricular fibrillation using
programmed ventricular stimulation techniques and the
HV interval is usually prolonged [30]. Signal averaged
electrocardiograms were reported to be abnormal in 22 of
27 cases in one study [30]. A positive signal averaged
electrocardiogram has been reported to have usefulness
to screen which patients are at high risk for the induction
of sustained VT/VF, by programmed electrical stimulation [41]. T wave alternans and QT duration do not

appear to have any predictive effect [41]. Molecular

biologic analysis can document SCN5A gene mutations
in 15 to 25% of patients [42].

Diagnosis
The classic Brugada syndrome is characterized by: (1) a
familial history of sudden cardiac death; (2) polymorphic
VT; (3) typical right ventricular conduction delay and
ST-segment elevation in V1-V3; (4) no evidence of structural heart disease by cardiac catheterization, echocardiography, magnetic resonance imaging, or myocardial biopsy; (5) worsening of ST-segment elevation by Class IA
or IC drugs; and (6) demonstration of a genetic defects
secondary to a mutation of SCN5A on chromosome 3.
Brugada patients may include symptomatic patients with
overt or transient ECG abnormalities, asymptomatic patients with abnormal or provoked ECG findings, and
asymptomatic family members. The Brugada syndrome
should be differentiated from arrhythmogenic right ventricular dysplasia, idiopathic ventricular fibrillation, polymorphic VT secondary to an inherited or acquired prolonged QT syndrome or and normal variants such as
patients with an RSR prime conduction pattern. Other
causes of ST-segment elevation including epicardial injury, pericarditis, early repolarization, and electrolyte abnormalities also must be ruled out.
Idiopathic ventricular fibrillation may account for up to
9% of unexpected sudden cardiac deaths and up to 50%
of sudden deaths occurring in patients with no demonstrable heart disease [1,2,36]. The onset of ventricular
tachycardia/fibrillation in the Brugada syndrome is typically not pause-dependent and may help differentiate
these patients from other forms of idiopathic ventricular
fibrillation or prolonged QT syndrome. Recently, bradycardic causes of death have been reported [43].

Prognosis and treatment

The mortality in symptomatic patients averages 10% per
year. Antiarrhythmic drugs such as beta-blockers and
amiodarone appear to have little use in prolonging survival. Class IC agents can be used to express the RBBB
and ST-segment elevation in latent cases. Asymptomatic
patients appear to have a better prognosis than symptomatic patients and possibly should not be treated as
aggressively [36,4547]. Atarashi et al. [36] reported that
after a three-year follow-up, the cumulative cardiac
event-free rate was 67.6% in the symptomatic versus
93.4% in the asymptomatic group (P = 0.0004). It has
been reported that asymptomatic patients with spontaneous electrocardiographic abnormalities are more likely
to develop symptoms during follow-up review than
asymptomatic patients with drug-induced changes [45].
The treatment of choice is implantation of an implantable cardioverter-defibrillator (ICD). Database collections of patients have demonstrated that an ICD statis-

22 Arrhythmias

tically prevents sudden cardiac death compared with no

therapy, beta-blockers, or amiodarone. In 19 patients
with Brugada syndrome treated with an ICD [44], who
were observed for 34.7 + 19.4 months, 46 episodes of
ventricular fibrillation attacks were documented in 7 of
19 (37%) of patients.
The role of electrophysiologic studies in treating patients
with Brugada syndrome remains controversial. In one
study of 76 patients, 50 patients had ventricular fibrillation induced by programmed electrical stimulation
[30]. The predictive accuracy of these findings was not
reported. In another study [43], programmed electrical
stimulation had a 50% positive predictive accuracy and a
46% negative predictive value in identifying patients at
risk for sudden death. The database collected by the
Brugadas suggests that patients with inducible sustained
ventricular tachycardia/fibrillation have a worse prognosis than in noninducible patients. Because of the presumed lower risk in noninducible patients, the role of
prophylactic ICD implantation remains controversial.
Recommendations for managing carriers of the disease is
equally difficult because asymptomatic outnumber clinically affected gene carriers [47].

13

Schott JJ, Alshinawi C, Kyndt F, et al.: Cardiac conduction defects associate

with mutations in SCN5A. Nat Genet 1999, 23:2021.

14

Wang Q, Shen J, Splawski I, et al.: SCN5A mutations associated with an

inherited cardiac arrhythmia, long QT syndrome. Cell 1995, 80:805811.

15 Naccarelli GV, Antzelevitch C. The Brugada syndrome: clinical, genetic, cellular, and molecular abnormalities. Am J Med 2001, 110:573581.

Up-to-date review of the basic electrophysiology and clinical manifestations of the

Brugada syndrome.
16

Yan GX, Antzelevitch C: Cellular basis for the electrocardiographic J wave.

Circulation 1996, 93:372379.

17

Yan GX, Antzelevitch C: Cellular basis for the Brugada Syndrome and other
mechanisms of arrhythmogenesis associated with ST segment elevation. Circulation 1999, 100:16601666.

18

Lukas A, Antzelevitch C: Phase 2 reentry as a mechanism of initiation of circus

movement reentry in canine epicardium exposed to simulated ischemia. The
antiarrhythmic effects of 4-aminopyridine. Cardiovasc Res 1996, 32:593
603.

19 Antzelevitch C: The Brugada syndrome: Ionic basis and arrhythmia mechanisms. J Cardiovasc Electrophysiol 2001;12:268-272.

Excellent overview of the ionic and cellular mechanisms associated with the Brugada syndrome.
20

Miyazaki T, Mitamura H, Miyoshi S, et al.: Autonomic and antiarrhythmic drug

modulation of ST segment elevation in patients with Brugada syndrome. J Am
Coll Cardiol 1996, 27:10611070.

21

Matsuo K, Shimizu W, Kurita T, et al.: Dynamic changes of 12-lead electrocardiograms in a patient with Brugada syndrome. J Cardiovasc Electrophysiol
1998, 9:508512.

22

Chinushi M, Aizawa Y, Ogawa Y, et al.: Discrepant drug action of disopyramide on ECG abnormalities and induction of ventricular arrhythmias in a patient with Brugada syndrome. J Electrocardiol 1997, 30:133136.

23

Priori SG, Napolitano C, Schwartz PJ, et al.: The elusive link between LQT3
and Brugada syndrome: the role of flecainide challenge. Circulation 2000,
102:945947.

24

Brugada R, Brugada J, Antzelevitch C, et al.: Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right
bundle branch block but structurally normal hearts. Circulation 2000,
101:510515.

25

Di Diego JM, Sun ZQ, Antzelevitch C: Ito and action potential notch are
smaller in left vs. right canine ventricular epicardium. Am J Physiol 1996,
271:H548H561.

26

Litovsky SH, Antzelevitch C: Rate dependence of action potential duration

and refractoriness in canine ventricular endocardium differs from that of epicardium: The role of the transient outward current. J Am Coll Cardiol 1989,
14:10531066.

27

Antzelevitch C: Ion channels and ventricular arrhythmias. Cellular and ionic

mechanisms underlying the Brugada syndrome. Curr Opin Cardiol 1999,
14:274279.

28

Antzelevitch C, Sicouri S, Litovsky SH, et al.: Heterogeneity within the ventricular wall: Electrophysiology and pharmacology of epicardial, endocardial
and M cells. Circ Res 1991, 69:14271449.

29
6

Belhassen B, Viskin S, Fish R, et al.: Effects of electrophysiologic-guided

therapy with Class IA antiarrhythmic drugs on the long-term outcome of patients with idiopathic ventricular fibrillation with or without the Brugada syndrome. J Cardiovasc Electrophysiol 1999, 10:13011312.

Antzelevitch C: The Brugada syndrome. J Cardiovasc Electrophysiol 1998,

9:513516.

30 Alings M, Wilde A: Brugada syndrome: clinical data and suggested pathophysiological mechanism. Circulation 1999, 99:666673.

Excellent overview of clinical manifestations and molecular mechanisms associated with the Brugada syndrome.

Rook MB, Alshinawi CB, Groenewegen WA, et al.: Human SCN5A gene
mutations alter cardiac sodium channel kinetics and are associated with the
Brugada syndrome. Cardiovasc Res 1999, 44:507517.

Brugada R, Roberts R: The molecular genetics of arrhythmias and sudden

death. Clin Cardiol 1998, 21:553560.

10

References and recommended reading

Papers of particular interest, published within the annual period of review,
have been highlighted as:

Of special interest

Of outstanding interest
1

Belhassen B, Viskin S: Idiopathic ventricular tachycardia and fibrillation. J

Cardiovasc Electrophysiol 1993, 4:356368.

Myerburg RJ: Sudden cardiac death in persons with normal (or near normal)
hearts. Am J Cardiol 1997, 79:39.

Brugada P, Brugada J: Right bundle branch block, persistent ST segment

elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome: a multicenter report. J Am Coll Cardiol 1992, 20:1391
1396.
Original description of the Brugada syndrome.
4

Chen Q, Kirsch GE, Zhang D, et al.: Genetic basis and molecular mechanisms for idiopathic ventricular fibrillation. Nature 1998, 392:293296.

Makita N, Shirai N, Wang DW, et al.: Cardiac Na(+) channel dysfunction in

Brugada syndrome is aggravated by beta(1)-subunit. Circulation 2000,
101:5460.

Gussak I, Antzelevitch C, Bjerregaard P, et al.: The Brugada syndrome: clinical, electrophysiological and genetic aspects. J Am Coll Cardiol 1999,
33:515.
Excellent overview of the genetic, electrophysiologic, and clinical aspects of the
Brugada syndrome.

31

Osher HL, Wolff L: Electrocardiographic pattern simulating acute myocardial

injury. Am J Med Sci 1953, 226:541545.

32

Nademanee K, Veerakul G, Nimmannit S, et al.: Arrhythmogenic marker for

the sudden unexplained death syndrome in Thai men. Circulation 1997,
96:25952600.

Bennett PB, Yazawa K, Makita N, et al.: Molecular mechanism for an inherited

cardiac arrhythmia. Nature 1995, 376:683685.

33

Otto CM, Tauxe RV, Cobb LA, et al.: Ventricular fibrillation causes sudden
death in Southeast Asian immigrants. Ann Intern Med 1984, 101:4547.

11

Veldkamp MW, Viswanathan PC, Bezzina C, et al.: Two distinct congenital

arrhythmias evoked by a multidysfunctional Na(+) channel. Circ Res 2000,
86:e91e97.

34

12

Towbin JA: Cardiac arrhythmias: the genetic connection. J Cardiovasc Electrophysiol 2000, 11:601602.

Brugada J, Brugada R, Brugada P: Right bundle-branch block and STsegment elevation in leads V1 through V3. A marker for sudden death in patients without demonstrable structural heart disease. Circulation 1998,
97:457460.

35

Tohyou Y, Nakazawa K, Ozawa A, et al.: A survey in the incidence of right

The Brugada syndrome Naccarelli et al. 23

bundle branch block with ST elevation among normal population. Jpn J Electrocardiol 1995, 15:223226.
36

Hermida JS, Lemoine JL, Aoun FB, et al.: Prevalence of the Brugada syndrome in an apparently healthy population. Am J Cardiol 2000, 86:9194.

37

Atarashi H, Ogawa S, Harumi K, et al: Three year follow-up of patients with

right bundle branch block and ST segment elevation in the right precordial
leads. J Am Coll Cardiol 2001, 37:19161920.
Report of the incidence of the electrocardiographic abnormality associated with
the Brugada syndrome in Japanese patients and the prognosis in asymptomatic
and symptomatic patients observed for three years.
38

39

40

Naccarella F, Lepera G, Iachetti F, et al.: Accurate noninvasive evaluation and

genetic screening could help in differentiating congenital Brugadas syndrome from the acquired one, secondary to right ventricular dysplasia cardiomyopathy. J Ital Cardiol 1999, 29:374379.
Takagi M, Aihara N, Kuribayashi S, et al.: Localized right ventricular morphological abnormalities detected by electron-beam computed tomography represent arrhythmogenic substrates in patients with the Brugada syndrome. Eur
Heart J 2001, 22:10321041.
Eckhardt L, Kirchhof P, Loh P, et al.: Brugada syndrome and supraventricular
tachyarrhythmias: a novel association? J Cardiovasc Electrophysiol 2001,
12:680685.

41

Ikeda T, Sakurada H, Sakabe K, et al.: Assessment of noninvasive markers in

identifying patients at risk in the Brugada syndrome: insight into risk stratification. J Am Coll Cardiol 2001, 37:16281634.
This paper defines the role of signal-averaged electrocardiograms in screening
Brugada patients for invasive electrophysiologic testing.
42

Priori SG, Napolitano C, Gasparini M, et al.: Clinical and genetic heterogeneity of right bundle branch block and ST- segment elevation syndrome: A
prospective evaluation of 52 families. Circulation 2000, 102:25092515.

43

Van Den Berg M, Wilde AM, Viersma JW, et al.: Possible bradycardic mode
of death and successful pacemaker treatment in a large family with features of
long QT syndrome type 3 and Brugada syndrome. J Cardiovasc Electrophysiol 2001, 12:630636.

44

Kakishita M, Kurita T, Matsuo K, et al.: Mode of onset of ventricular fibrillation

in patients with Brugada syndrome detected by implantable cardioverter defibrillator therapy. J Am Coll Cardiol 2000, 36:16461653.

45

Gussak I, Bjerregaard P, Hammill SC: Clinical diagnosis and risk stratification

in patients with Brugada syndrome. J Am Coll Cardiol 2001, 37:16351638.

46

Brugada P, Brugada R, Brugada P: Sudden death in high-risk family members: Brugada syndrome. Am J Cardiol 2000, 86:40K43K.

47

Priori SG: Long QT and Brugada syndromes: From genetics to clinical management. J Cardiovasc Electrophysiol 2000, 11:11741178.